CN105960401B - Pyridyl group or pyrimidyl compounds - Google Patents

Pyridyl group or pyrimidyl compounds Download PDF

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CN105960401B
CN105960401B CN201480062769.4A CN201480062769A CN105960401B CN 105960401 B CN105960401 B CN 105960401B CN 201480062769 A CN201480062769 A CN 201480062769A CN 105960401 B CN105960401 B CN 105960401B
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halogenated
amino
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CN105960401A (en
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N.戈夫里
F.波特拉
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Swiss Iran Animal Health Care Co Ltd
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Abstract

The present invention relates to the compound of logical formula (I) or its physiologically acceptable salt

Description

Pyridyl group or pyrimidyl compounds
Invention field
The present invention relates to new pyridine base or pyrimidyl compounds, their preparation method, they in prevention animal, especially Be purposes in endoparasite in productive livestock and domestic animal and thereon and containing one kind in these compounds or A variety of Pesticidal combinations.
Summary of the invention
The present invention relates to the noval chemical compound of following formula or its physiologically acceptable salt
Wherein Z1And Z2It is N or CR each independently1’；
R1And R1’It is H, halogen, cyano, nitro, C independently of one another1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alcoxyl Base, C1-C3Halogenated alkoxy, C1-C4Alkyl sulfenyl, halogenated-C1-C4Alkyl sulfenyl, SF5, amino, N- mono--or N, N- bis-- C1-C4Alkyl amino, amino-sulfonyl, N- be mono--or bis--C of N, N-1-C4Alkyl amino sulfonyl, N- be mono--or bis--halogen of N, N- Generation-C1-C4Alkyl amino sulfonyl, C1-C4Alkyl sulphonyl, C1-C4Alkyl sulphinyl, C1-C4Alkyl sulphonyl ammonia Base, halogenated-C1-C4Alkyl sulphonyl, halogenated-C1-C4Alkyl sulphinyl, halogenated-C1-C4Alkyl sulfonyl-amino or benzyl Base sulfuryl amino；
Q is Ar1Or-C (O)-(O)m-R2,
M is 0 or 1；R2It is C1-C6Alkyl or C3-C8Cycloalkyl；
Ar1It is (i) by the 1 or 2 identical or different phenyl replaced selected from following substituent group：Halogen, cyano, Nitro, C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkyl sulfenyl, halogen Generation-C1-C4Alkyl sulfenyl, SF5, amino, N- it is mono--or bis--C of N, N-1-C4Alkyl amino, amino-sulfonyl, N- be mono--or N, N- Two-C1-C4Alkyl amino sulfonyl, N- be mono--or N, N- bis--halogenated-C1-C4Alkyl amino sulfonyl, C1-C4Alkyl sulfonyl Base, C1-C4Alkyl sulphinyl, C1-C4Alkyl sulfonyl-amino, benzylsulphonyl amino, halogenated-C1-C4Alkyl sulfonyl Base, halogenated-C1-C4Alkyl sulphinyl and halogenated dioxa cyclopentenyl；Or (ii) heteroaryl, it is selected from 2-, 3- or 4- Pyridyl group and 2- or 3- thienyls, it is respectively unsubstituted or for example by methyl, ethyl, halogen, CF3Or carboxyl substitution；
Ar2It is by 1 to 3 identical or different phenyl replaced selected from following substituent group：Halogen, cyano, nitro, C1- C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkyl sulfenyl, halogenated-C1-C4Alkane Base sulfenyl, SF5, amino, N- it is mono--or bis--C of N, N-1-C4Alkyl amino, amino-sulfonyl, N- be mono--or bis--C of N, N-1-C4Alkane Base amino-sulfonyl, N- be mono--or N, N- bis--halogenated-C1-C4Alkyl amino sulfonyl, C1-C4Alkyl sulphonyl, C1-C4Alkane Base sulfinyl, C1-C4Alkyl sulfonyl-amino, benzylsulphonyl amino, halogenated-C1-C4Alkyl sulphonyl, halogenated-C1- C4Alkyl sulphinyl and halogenated dioxa cyclopentenyl；
L1It is the bifunctional linker group of following formula
L2It is the bifunctional linker group of following formula
A and B is the C for including two N- atoms respectively each independently3-C8Miscellaneous-cycloalkylidene (hetero- ) or C cycloalkylene5-C10Miscellaneous-sub- bicyclic alkyl (hetero-bicycloalkylene), it is respectively unsubstituted or By C1-C2Alkyl replaces；
A1、A2、B1And B2It is the C for including N- atoms respectively each independently3-C8Miscellaneous-cycloalkylidene；
R and R ' is H or C independently of one another1-C4Alkyl.
The present invention also provides the compound or its salts comprising formula (I) and at least one to dilute selected from surfactant, solid The composition of the additional component of agent and liquid diluent.
In one embodiment, the present invention also provides for preventing the composition of parasite, particularly endoparasite, The compound or its salt and at least one that the composition includes the formula (I) of biologic effective dose are selected from surfactant, solid The additional component of diluent and liquid diluent, at least one the composition optional further contains biologic effective dose are additional Bioactive compound or agent.
Detailed description of the invention
In described above, exclusive use or the term used in compound word such as " alkyl sulfenyl " or " halogenated alkyl " " alkyl " includes linear or branched alkyl group, and such as methyl, ethyl, n-propyl, isopropyl or different butyl, amyl or hexyl are different Structure body.
" alkoxy " includes such as methoxyl group, ethyoxyl, positive propoxy, isopropoxy and different butoxy, amoxy And hexyloxy isomers." alkyl sulfenyl " includes branched-chain or straight-chain alkyl thio groups, such as methylsulfany, ethylsulfanyl and not Same propyl sulfenyl, butyl sulfenyl, pentylthio and hexyl sulfenyl isomers.
The two kinds of enantiomters of " alkyl sulphinyl " including alkyl sulphinyl.The example packet of " alkyl sulphinyl " Include CH3S(O)-、CH3CH2S(O)-、CH3CH2CH2S(O)-、(CH3)2CHS (O)-and different butylsulfinyl isomers.
The example of " alkyl sulphonyl " includes CH3S(O)2-、CH3CH2S(O)2-、CH3CH2CH2S(O)2-、(CH3)2CHS (O)2And different butyl sulfonyl isomers.
" N- alkyl aminos ", " N, N- di-alkyl amino " etc. are defined similar to example above.
" cycloalkylidene " includes, for example, cyclopropylidene, sub- cyclobutyl, cyclopentylene, cyclohexylidene, cycloheptylidene or Asia Cyclooctyl, preferably cyclopropylidene, sub- cyclobutyl, cyclopentylene, cyclohexylidene, and particularly cyclopentylene, cyclohexylidene.
Example comprising 1 or 2 heteroatomic miscellaneous-sub- bicycloalkyl radicals is the group of following formula
Wherein r and s is integer 0,1 or 2 independently of one another.The example of preferred miscellaneous sub- bicycloalkyl radicals is spiral shell-phenodiazine Miscellaneous-C5-C10Alkylidene, such as 1,6- or 2,6- diaza spiro-[3.3] heptamethylene, 1,6- or 2,6- diaza spiro-[3.4] it is sub- Octyl group or 1,7- or 2,7- diaza spiros-[4.4] nonylene.
The term " halogen " for being used alone or being used in compound word such as " halogenated alkyl " includes fluorine, chlorine, bromine or iodine.This Outside, when in compound word such as " halogenated alkyl " in use, the halogen atom part that the alkyl can be may be the same or different Or all substitutions.The example of " halogenated alkyl " includes F3C-、ClCH2-、CF3CH2And CF3CCl2-.Term " halogenated cycloalkyl ", " halogenated alkoxy ", " haloalkylthio " etc. are defined similar to term " halogenated alkyl ".The example of " halogenated alkoxy " Including CF3O-、CCl3CH2O-、HCF2CH2CH2O- and CF3CH2O-.The example of " haloalkylthio " includes CCl3S-、CF3S-、 CCl3CH2S- and ClCH2CH2CH2S-.The example of " alkylsulfinyl " includes CF3S(O)-、CCl3S(O)-、CF3CH2S (O)-and CF3CF2S(O)-.The example of " halogenated alkyl sulfonyl " includes CF3S(O)2-、CCl3S(O)2-、CF3CH2S(O)2And CF3CF2S(O)2-。
The sum of carbon atom is with " C in substituent groupi-Cj" prefix expression, wherein i and j are integers.For example, C1-C4Alkyl sulphur Acyl group represents methyl sulphonyl to butyl sulfonyl；C2Alkoxyalkyl represents CH3OCH2；C3Alkoxyalkyl represents for example CH3CH(OCH3)、CH3OCH2CH2Or CH3CH2OCH2；And C4Alkoxyalkyl is represented by the alcoxyl in total containing four carbon atom The various isomers of the alkyl of base substitution, example include CH3CH2CH2OCH2And CH3CH2OCH2CH2-。
It is described when compound can be replaced with the number for showing the substituent group more than 1 lower target substituent group Substituent group (when they are more than 1) is independently selected from the group of the substituent group of definition, such as (R2)n, n is 1 or 2.
" aromatic " shows each annular atom substantially in same level and with the p- tracks perpendicular to plane of a loop, and And wherein (4n+2) pi-electron (wherein n is positive integer) is related to ring, to meet H ckelShi rules.
In the compound of formula (I), R1And R1’It is preferably H, halogen, cyano, C each independently1-C2Alkyl, C1-C2- Halogenated alkyl, C1-C2Alkoxy, C1-C2Halogenated alkoxy, C1-C2Alkyl sulfenyl, amino or N- it is mono--or bis--C of N, N-1- C2Alkyl amino, more preferable H, halogen, cyano, C1-C2Alkyl, C1-C2Alkoxy, C1-C2Bis--C of alkyl sulfenyl or N, N-1- C2Alkyl amino, and particularly H, cyano, methyl or methoxy.R1Preferably H, cyano, methyl or methoxy, more preferable H or Cyano, and particularly H.R1’Preferably H, cyano, methyl or methoxy, more preferable H, cyano or methoxyl group, and particularly H.
According to an embodiment, Z1It is N and Z2It is CR1', wherein for R1’, meaning given above and preferred embodiment It is applicable in.Most preferably, Z1It is N and Z2It is CH.
According to another embodiment, Z1And Z2It is N.
According to another embodiment, Z1It is CR1’And Z2It is N, wherein for R1’, meaning given above and preferably side Case is applicable in.Most preferably, Z1It is CH and Z2It is N.
According to another embodiment, Z1And Z2It is CR each independently1’, wherein for R1’, it is applicable in given above contain Justice and preferred embodiment, are particularly CH.
Ar1It is preferably by the 1 or 2 identical or different phenyl replaced selected from following substituent group as phenyl：Halogen Element, cyano, nitro, C1-C2Alkyl, C1-C2Halogenated alkyl, C1-C2Alkoxy or C1-C2Halogenated alkoxy.It is especially preferred Phenyl group Ar1It is by the 1 or 2 identical or different phenyl replaced selected from following group：Halogen, cyano and C1-C2- Halogenated alkyl, particularly chlorine, fluorine, cyano or CF3.Particularly preferred phenyl group Ar1It is by CF3Mono-substituted phenyl, especially It is 4-CF3Phenyl.
Preferred heteroaryl groups Ar1It is 2-, 3- or 4- pyridyl group, it is unsubstituted or for example by methyl, ethyl, halogen Element, CF3Or carboxyl substitution.Particularly preferred heteroaryl groups Ar1It is 2- or 3- pyridyl groups, it is unsubstituted or by halogen or CF3 Substitution, especially 5-CF3Pyridine -2- bases or 6-CF3Pyridin-3-yl.
R2Preferably C1-C4Alkyl or C3-C6Cycloalkyl, particularly tertiary butyl, cyclopropyl, cyclobutyl, cyclopenta or ring Hexyl, particularly tertiary butyl or cyclopropyl, especially tertiary butyl.
Preferred group Q is identical or different selected from chlorine, fluorine, cyano or CF by 1 or 23Group substitution benzene Base：It is unsubstituted or by halogen or CF3Substituted 2- or 3- pyridyl groups；Either-C (O)-(O)0-1-R2, wherein R2It is C1-C4- Alkyl or C3-C6Cycloalkyl.Particularly preferred group Q is 4-CF3Phenyl, 5-CF3Pyridine -2- bases, 6-CF3Pyridine -3- Base ,-C (O)-O- tertiary butyls or-C (O)-cyclopropyl.
Ar2It is preferably by the 1 or 2 identical or different phenyl replaced selected from following substituent group as phenyl：Halogen Element, cyano, nitro, C1-C4Alkyl, C1-C2Halogenated alkyl, C1-C2Alkoxy, C1-C2Halogenated alkoxy, C1-C2Alkyl Sulfenyl, C1-C2Haloalkylthio, C1-C2Alkyl sulphonyl, halogenated-C1-C2Alkyl sulphonyl, amino, N- be mono--and N, N- Two-C1-C4Alkyl amino, amino-sulfonyl and C1-C2Alkyl amino sulfonyl.Even more preferably phenyl group Ar2Be by The 1 or 2 identical or different phenyl replaced selected from following group：Halogen, cyano, nitro, C1-C4Alkyl, C1-C2- Halogenated alkyl, C1-C2Alkoxy, C1-C2Halogenated alkoxy, C1-C2Haloalkylthio, C1-C2Alkyl sulphonyl, it is halogenated- C1-C2Alkyl sulphonyl, amino and C1-C2Alkyl amino sulfonyl.Particularly preferred phenyl group Ar2It is by 1 or 2 The identical or different phenyl replaced selected from following group：Halogen, cyano, nitro, C1-C2Halogenated alkyl, C1-C2It is halogenated Alkoxy or C1-C2Haloalkylthio.Especially preferred phenyl group Ar2It is identical or different selected from following by 2 The phenyl of group substitution：Fluorine, cyano, nitro and CF3.Particularly preferred group Ar2Example be 4- nitros -3-CF3Phenyl, 4- cyano -2-CF3Phenyl, 4- cyano -3-CF3Phenyl, bis--CF of 3,4-3Phenyl, 4-CF3- 3- fluorophenyls, 3-CF3- 4- fluorobenzene Base, particularly 4- cyano -3-CF3Phenyl.
Group L1And L2Can be it is identical or different, it is particularly different.
About group L1, it is applicable in following preferred embodiment：
Variables A preferably unsubstituted miscellaneous-cycloalkylidene comprising two N- atoms or miscellaneous-sub- bicyclic alkyl base respectively Group, especially C3-C6Miscellaneous-cycloalkylidene or C5-C8Miscellaneous-sub- bicyclic alkyl.
The preferred linker L of formula (IIa)1It is group
Wherein s and r is integer 1 or 2 each independently, and r' is integer 0,1 or 2；In above formula, one of s and r are preferably 1, and another is 1 or 2, and r' is preferably 1 or 2, especially for 1.
The example of the bifunctional linker of formula (IIa) is
。
The preferred bifunctional linker of formula (IIb) is group
Wherein s' is integer 0,1 or 2, and R is H or methyl, particularly H.
The example of the bifunctional linker of formula (IIb) is
。
The preferred bifunctional linker of formula (IIc) is group
Wherein s' is integer 0,1 or 2, particularly 1 or 2, and R is H or methyl.
The example of the suitable bifunctional linker of formula (IIc) is group
。
Particularly preferred group L1It is group。
About group L2, it is applicable in following preferred embodiment：
B is preferably unsubstituted miscellaneous-cycloalkylidene comprising two N- atoms or miscellaneous-sub- bicycloalkyl radicals, especially C3-C6Miscellaneous-cycloalkylidene, particularly C3-C4Miscellaneous-cycloalkylidene.
The preferred bifunctional linker L of formula (IIIa)2It is the group of following formula
Wherein r'' is 0 or 1, particularly group。
The preferred bifunctional linker L of formula (IIIb)2It is the group of following formula
Wherein s'' is integer 0,1 or 2, and R' is H or methyl, particularly H；Especially
Group。
The preferred bifunctional linker L of formula (IIIc)2It is the group of following formula
Wherein s' is integer 0,1 or 2, particularly 1 or 2, and R' is H or methyl, particularly H.Example is group。
Particularly preferred group L2Example be group
。
One group of preferred compound according to the present invention has following formula
Wherein for R1、R2、m、L1、L2、Z1、Z2And Ar2, each self application meaning given above and preferred embodiment.
Another group of preferred compound according to the present invention has following formula
Wherein for R1、Ar1、Ar2、L1、L2、Z1And Z2, each self application meaning given above and preferred embodiment or its Physiologically acceptable salt.
The preferred embodiment of the present invention is related to the compound or its physiologically acceptable salt of formula (I), Middle Z1And Z2It is N or CR each independently1’；
R1And R1’It is H, cyano, methyl or methoxy, particularly H independently of one another；
Q is identical or different selected from chlorine, fluorine, cyano or CF by 1 or 23Group substitution phenyl：It is unsubstituted Or by halogen or CF3Substituted 2- or 3- pyridyl groups；Or-C (O)-(O)0-1-R2, wherein R2It is C1-C4Alkyl or C3-C6Ring Alkyl；
Ar2It is identical or different selected from fluorine, cyano, nitro and CF by 23Group substitution phenyl；
L1It is group
L2It is group。
Another preferred embodiment of the present invention is related to the compound or its physiologically acceptable salt of following formula,
Wherein Q is 4-CF3Phenyl, 5-CF3Pyridine -2- bases, 6-CF3Pyridin-3-yl ,-C (O)-O- tertiary butyls or-C (O)-cyclopropyl；
Z1It is N or CH, particularly N；
Z2It is N or CH, particularly CH；
L1It is group
L2It is group
R3It is CF3；And R3’It is cyano or nitro, particularly cyano.
The compound of formula (I) can be prepared for example by following：Make the compound of following formula
Wherein R1、Z1And Z2Respectively as defined above, and X1And X2It is leaving group each independently, such as halogen, especially It is chlorine；
In succession with each compound of following formula
Wherein Q, Ar2、L1And L2Respectively as defined above；
In a way known, the aromatic nucleophilic of the pyridine of the formula (IV) or pyrimidine substitution particularly on being suitable for In medium, reacted.Reaction condition changes according to the reactivity of the compound of formula (Va) or (Vb) used.With with end End primary amino group or the formula (Va) of secondary amino group or the compound of (Vb) are compared, formula (Va) or (Vb) with terminal hydroxyl or sulfydryl Compound is easier to react, such as in aprotic dipolar solvents at room temperature with the compound of formula (IV), preferably in dipole In aprotic solvent at higher temperature such as 70 to 120 DEG C, optionally in catalyst such as Pd (OAc)2, the presence such as RuPhos In the case of react.The specific example of these aromatic nucleophilie nuclear substituting reactions of haloperidid class and halogen pyrimidines is known , for example, from J.Med.Chem. 2011, Vol 54, p.6563-6585, J.Med.Chem. 2009, Vol 52, Or Chem.Science 2011, Vol.2, p.5999-6011 it is p.57-68 known.
The compound of formula (IV) is known or can be obtained by method known per se.The chemical combination of formula (Va) and (Vb) Object again may be by method known per se and obtain, such as pass through halogenated compound Ar1Or Ar2With compound H-L1- H or H- L2The aromatic nucleophilic of H replaces to obtain.
The salt of compound I can generate in a known way.The acid-addition salts of compound I, for example, can be by using suitable acid Or suitable ion exchange reagent is handled and is obtained, and can be by using suitable alkali or suitable ion exchange reagent with the salt of alkali It handles and obtains.
The salt of compound I can be converted into free compound I by conventional methods, and acid-addition salts are for example by using suitable Alkaline compositions or handled with suitable ion exchange reagent, and with the salt of alkali for example by using suitable acid or suitably from Son exchanges reagent processing.
The salt of compound I can be converted into other salt of compound I in a known way；Acid-addition salts can be converted into for example Other acid-addition salts, for example, by a suitable solvent with suitable metal salt (such as sour sodium, barium or silver salt, for example, with Silver acetate) processing inorganic acid salt (such as hydrochloride), in the suitable solvent, gained inorganic salts, such as silver chlorate are It is insoluble and be therefore precipitated out from reaction mixture.
Depending on method and/or reaction condition, the compound I with salt-forming characteristics can in a free form or the shape with salt Formula obtains.
Compound I in the form of their hydrate can also obtain and/or can also include other solvents, such as If necessary for the crystallization of existing compound in solid form.
The compound of Formulas I can exist optionally as optics and/or geometric isomer or as its mixture.The present invention It is related to both pure isomer and all possible heterogeneous mixture, and should so understands above and below, even if in each feelings Stereochemical details are not specifically mentioned under condition.
The diastereoisomeric mixture of formula (I) compound that can be obtained by the method or in another way can be with Physical-chemical differences in a known way based on their component are separated into pure diastereoisomer, for example, by fractional crystallization, Distillation and/or chromatography.
The mixture for the enantiomter that can accordingly obtain is split as pure isomer can to realize by known method, Such as by being recrystallized from optical activity solvent, by the chromatography on chiral sorbent, such as by acetylcellulose High pressure liquid chromatography (HPLC) (HPLC) with the help of appropriate microorganism, is cracked by using specific immobilised enzymes, is wrapped by being formed Polymerisable compounds, such as using chiral crown ether, only a kind of enantiomter is thus complexed.
Compound (I) according to the present invention has significant wide activity profile, and is for warm-blooded animal, especially domestic animal With control of insect in domestic animal and thereon, including being particularly the anti-of endoparasite and vermin, especially worm The valuable active constituent controlled, at the same it is well tolerable by warm-blooded animal and fish.
In the context of the present invention, vermin is interpreted as particularly insect, acarid and tick worm.These include with Lower purpose insect：Lepidoptera (Lepidoptera), coleoptera (Coleoptera), Homoptera (Homoptera), Heteroptera (Heteroptera), Diptera (Diptera), Thysanoptera (Thysanoptera), Orthoptera (Orthoptera), Anoplura (Anoplura), Siphonaptera (Siphonaptera), Mallophaga (Mallophaga), Thysanoptera (Thysanura), Isoptera (Isoptera), Corrodentia (Psocoptera) and Hymenoptera (Hymenoptera).However, it is possible to specifically mentioned posts in vitro It is infested be perplex humans and animals and carry pathogen those, such as flies such as housefly (Musca domestica), shrub Clump fly (Musca vetustissima), autumn fly (Musca autumnalis), anthomyia canicularis (Fannia canicularis)、 Sarcophaga carnaria (Sarcophaga carnaria), lucilia cuprina (Lucilia cuprina), bomb fly (Hypoderma bovis), heel fly (Hypoderma lineatum), green alga gold fly (Chrysomyia chloropyga), fell fly (Dermatobia hominis), cochliomyia bominovorax (Cochliomyia hominivorax), Gasterophilus intestinalis (Gasterophilus intestinalis), Oestrus ovis (Oestrus ovis), tatukira (Stomoxys calcitrans), Haematobia irritans (Haematobia irritans) and mosquito class (Nematocera (Nematocera)), such as Dulicidae (Culicidae), Simulidae (Simuliidae), Moth files (Psychodidae) and blood-sucking parasites, such as flea class, such as ctenocephalides felis (Ctenocephalides felis) and ctenocephalides canis (Ctenocephalides canis) (cat and dog flea class), Xanthopsyllacheopis (Xenopsylla cheopis), cause itch Pulex irritans (Pulex irritans), chigo (Dermatophilus penetrans), lice class, such asDamalina ovis, humanlice (Pediculus humanis), sting fly and horse botfly (Tabanidae (Tabanidae)), Chrysozona (Haematopota spp.), Zhu for example Plovers fiber crops horsefly (Haematopota pluvialis),TabanideaBelong to (Tabanidea spp.), such asTabanus nigrovittatus, Chrysops (Chrysopsinae Spp.), such as chrysops cecutiens (Chrysops caecutiens), tsetse fly (tsetse flies), such as Glossina (species of Glossinia), biting insect, particularly blattaria, such as Cockroach (Blatella germanica), oriental cockroach (Blatta orientalis), American cockroach (Periplaneta americana), mite class, such as Dermanyssus gallinae (Dermanyssus gallinae), itch mite (Sarcoptes scabiei), psoroptes communis (Psoroptes ovis) and Psorergates (Psorergates spp.) and the last but simultaneously tick class of not the least important.The latter belongs to Acarina.The representative of known tick class Be for example Boophilus (Boophilus), Amblyomma (Amblyomma), Anocentor (Anocentor), Dermacentor (Dermacentor), Haemaphysalis (Haemaphysalis), Hyalomma (Hyalomma), Isodesspp (Ixodes), fan leather tick Belong to (Rhipicentor), ox tick category (Margaropus), Rhinpicephalus (Rhipicephalus), Argas (Argas), Otiobius (Otobius) and Ornithodoros (Ornithodoros) etc., warm-blooded animal is preferably invaded and harassed, including farm Animal, such as ox, pig, sheep and goat, poultry such as chicken, turkey and goose, fur-bearing animal such as ermine, fox, chinchilla, rabbit Deng and domestic animal such as cat and dog, somebody.
The compound of formula (I) according to the present invention to show normal sensitivity animal pest and show tolerance that All or each stages of development of a little pests (member of such as insect and Acarina) are also effective.The active material of the present invention Insecticidal, ovicidal and/or miticidal effect can directly be shown with itself, i.e., kill evil immediately or after some time has elapsed Worm, such as when husking generation or by destroying their ovum or showing indirectly, such as reduce the number of oviposition and/or incubate Change rate, there is the good effect corresponding at least 50 to 60% killing rate (death rate).
Compound (I) can be also used for the Flesh flies of anti-sanitary insect pest, especially Diptera (Diptera) (Sarcophagidae)、AnophilidaeWith Dulicidae (Culicidae)；Orthoptera (Orthoptera), Dictyoptera (Dictyoptera) (such as Blattidae (Blattidae)) and Hymenoptera (Hymenoptera) (for example, Formicidae (Formicidae))。
Particularly, the compound is effective to worm, and the wherein Nemata of endobiosis and Trematoda can cause lactation to be moved Object and the serious disease of poultry, the mammal and poultry such as sheep, pig, goat, ox, horse, donkey, dog, cat, cavy or outer Come birds, particularly sheep or especially ox.The Typical nematodes of the indication are：Haemonchus (Haemonchus), Mao Yuan Turbatrix (Trichostrongylus), ostertagi category (Ostertagia), Nematodirus (Nematodirus), it is ancient Cypress Turbatrix (Cooperia), Ascaris (Ascaris), Bunostomum (Bunostonum), oesophagostomum (Oesophagostonum), Chabertia category (Charbertia), Trichocephalus (Trichuris), Strongylus (Strongylus), Trichonema (Trichonema), Dictyocaulus (Dictyocaulus), Hepaticola (Capillaria), Heterakis (Heterakis), Belascaris (Toxocara), Ascaridia (Ascaridia), point Buttock line Eimeria (Oxyuris), Ancylostoma (Ancylostoma), Ancylostoma (Uncinaria), Toxascaris (Toxascaris), Dirofilaria (Dirofilaria), Acanthocheilonema (Acanthocheilonema) and parascris (Parascaris).Trematoda particularly including Fascioloides (Fasciolideae), especially Fasciola hepatica (Fasciola hepatica)。
Can be with astonishing and unexpectedly show, the compound of formula (I) is for many substance tolerances Nematode has abnormal efficient.This can be tested by LDA and be for example proven in mongolian gerbil in vivo in vitro.It is aobvious Show kill haemonchus contortus (Haemonchus contortus) or trichostrongylus colubriformis (Trichostrongylus colubriformis) sensitive strain active material the correspondence strain that is resistant in prevention to benzimidazole or levamisol of amount In be also effective enough.
Nematodirus (Nematodirus), Cooperia (Cooperia) and oesophagostomum (Oesophagostonum) certain pests invade and harass host animal enteron aisle, and Haemonchus (Haemonchus) and it is difficult to understand this Special Turbatrix (Ostertagia) other pests it is parasitic under one's belt, Dictyocaulus (Dictyocaulua) those pests exist It is parasitic in lung tissue.Filariidae (Filariidae) and Filamentous section (Setariidae) parasite be found in internal cell tissue In organ (such as heart, blood vessel, lymphatic vessel and subcutaneous tissue).Particularly noteworthy parasite is heartworm-dog of dog Evil filaria (Dirofilaria immitis).The compound of formula (I) is very effective these parasites.
Those from Cestoda (Cestoda) (tapeworm), example can be further included by the pest that the compound of Formulas I prevents As Mesocestoididae (Mesocestoidae), especially Mesocestoides (Mesocestoides), hole silk ribbon is particularly grown in line Worm (M. lineatus)；Multiple holes tapeworm section (Dilepidide), especially diphlidium caninum (Dipylidium caninum)、 Joyeuxiella (Joyeuxiella spp), particularlyJoyeuxiella pasqualiAnd Diplopylidium (Diplopylidium spp) and with tapeworm section (Taeniidae), especially taenia pisiformis (Taenia pisiformis), taenia cervi (Taenia cervi), taenia ovis (Taenia ovis), taenia hydatigena (Taneia hydatigena), multiceps (Taenia multiceps), taenia crassicollis (Taenia taeniaeformis), zigzag Tapeworm (Taenia serialis) and Echinococcus (Echinocuccus spp), most preferably taenia hydatigena (Taneia hydatigena), taenia ovis (Taenia ovis), multiceps (Taenia multiceps), taenia serrata (Taenia serialis)；Echinococcus granulosus (Echinocuccus granulosus) and Echinococcus granulosus (Echinococcus granulosus) and Echinococcus multilocularis (Echinococcus multilocularis) and multiceps (Multiceps multiceps)。
Most particularly, taenia hydatigena (Taenia hydatigena), taenia pisiformis (T. pisiformis), taenia ovis (T. ovis), taenia crassicollis (T. taeniaeformis)、Multiceps (Multiceps multiceps)、Joyeuxiella pasquali, diphlidium caninum (Dipylidium caninum), Mesocestoides (Mesocestoides spp), Echinococcus granulosus (Echinococcus granulosus) and Echinococcus multilocularis (E. multilocularis) and Dirofilaria (Dirofilaria ssp.), Ancylostoma (Ancylostoma ssp.), Belascaris (Toxocara ssp) and/or fox hair filaria (Trichuris vulpis) prevented simultaneously on dog and cat or in it. It is also preferable that ctenocephalides felis (Ctenocephalides felis) and/or ctenocephalides canis (C.canis) with it is above mentioned Nemata and tapeworms are prevented simultaneously.
In addition, the compound of formula (I) is suitable for preventing people's pathogenic parasite.In these, the typical case in alimentary canal is come across Representative be Ancylostoma (Ancylostoma), Necator (Necator), Ascaris (Ascaris), Strongyloides (Strongyloides), trichina cystica category (Trichinella), Hepaticola (Capillaria), Trichocephalus (Trichuris) and Enterobius (Enterobius) those.The compound of the present invention is each to coming across in blood, organizing to neutralize In kind of organ from Filariidae (Filariidae) Wu Ce Filarias (Wuchereria), Bu Luge Filarias (Brugia), Onchocerca (Onchocerca) and Lip river Ah's Filaria (Loa) and the imperial nematode to especially invading and harassing gastrointestinal tract Belong to (Dracunculus) and Strongyloides (Strongyloides) and trichina cystica category (Trichinella) parasite It is effective.
The good insecticidal of the compound of formula (I) according to the present invention corresponds at least 50- of mentioned pest 60% death rate.Particularly, the compound of formula (I) has the prominent extremely long effect duration.
The compound of formula (I) is preferably in unmodified form or preferably together with adjuvant conventional use of in formulation art Using therefore can handling in known manner, to obtain such as missible oil (emulsifiable concentrates), can be straight Connect the microcapsules in diluted solution, dilute emulsion, soluble powder, particle or polymeric material.As the composition, using side Method is selected according to target and popularity.
Preparation, that is, active constituent or these active constituents containing formula (I) and other active constituents and optional solid or liquid Medicament, product or the composition of the combination of body adjuvant, prepare in a way known, for example, by by active constituent with exhibition Composition, such as mixes and/or grinds closely with solvent, solid carrier and optional surface active cpd (surfactant) It grinds and prepares.
The solvent can be：Alcohols, such as ethyl alcohol, propyl alcohol or butanol and glycols and their ether and ester, such as Propylene glycol, dipropylene glycol, ethylene glycol, ethylene glycol monomethyl or-ethylether, ketone, such as cyclohexanone, isophorone or double third Keto-alcohol (diacetanol alcohol), intensive polar solvent, such as n-methyl-2-pyrrolidone, dimethyl sulfoxide or dimethyl methyl Amide or water, plant oil, such as rape oil, castor oil, coconut oil or soybean oil and (if appropriate) silicone oil.
The preferred administration form used on warm-blooded animal in the prevention of worm includes solution, lotion, suspension (clothes Agent (drenches)), food additive, powder, tablet (including effervescent tablet), bolus, capsule, microcapsules and pour (pour-on) preparation, it is thus necessary to consider the physiological compatibility of formulation excipients.
Adhesive for tablet and bolus (boli) can be the natural materials of the polymerization of chemical modification, dissolve in (such as methylcellulose, carboxymethyl cellulose, ethyl hydroxy ethyl are fine for water or alcohol, such as starch, cellulose or protein derivatives Tie up element, albumen zeins, gelatin etc.) and the polymer that synthesizes, such as polyvinyl alcohol, polyvinylpyrrolidone Deng.The tablet also contains filler (for example, starch, microcrystalline cellulose, sugar, lactose etc.), glidant and disintegrant.
If anti-anthelminthic exists in the form of feed concentrate, used carrier is such as performance feeds, feed Cereal or protein concentrate.Besides the active ingredients, such feed concentrate or composition can also contain additive, dimension life Element, antibiotic, chemotherapeutics or other insecticides mainly press down bacteriocin, fungistat, decoquinate or even hormone system Agent, the substance with anabolic action promote growth, influence the meat of slaughtered animals or in another way to organism Advantageous substance.If the active constituent of the composition or the Formulas I wherein contained is added directly to feed or drinks tank, The feed or drink then prepared contain the active constituent of the concentration of preferably from about 0.0005 to 0.02 weight % (5-200 ppm).
The compound of formula (I) according to the present invention can be used alone or be used with other biocide combinations.They can With with the insecticide composition with same range activity, such as with increase activity or with the substance group with another range activity It closes, such as to widen field of activity.So-called pest repellant can also rationally be added.It is posted in vivo if field of activity extended to It is infested, such as worm, then the compound of Formulas I is suitably combined with the substance with endobiosis characteristic.Certainly, they also may be used To be applied in combination with antibacterial compositions.Since the compound of Formulas I is adulticide, i.e., since they are particularly to the manhood Target parasites are effective, so the insecticide that the parasite in brephic is attacked in addition instead may be very favorable.With the party Formula, the parasite of the very big economic loss of those generations that largest portion will be covered.Moreover, the effect will essentially contribute to avoid The formation of tolerance.Many combinations can also cause to act synergistically, you can to reduce the total amount of active constituent, this sees from ecology It is desired from the point of view of point.Preferred group and especially preferred combined partner of combined partner are named below, thus in addition to the change of formula (I) It closes except object, combination can also be containing one or more in these companions.
Suitable companion in the mixture can be biocide, for example, the insecticide with different activities mechanism and Acaricide, this is known to the skilled in the art, such as chitin synthesis inhibitors, growth regulator；As juvenile hormone Active constituent；Active constituent as adulticide；Broad-band insecticides, broad spectrum acaricides and nematicide；Also many institutes Known anti-anthelminthic and the substance of prevention insect and/or acarian, pest repellant, desorbing agent (detacher) and synergist.
Suitable insecticide and acaricidal non-limiting examples are in the 18-21 pages of the chemical combination of WO 2009/071500 Mentioned in object 1-284.
The non-limiting examples of suitable anti-anthelminthic in WO 2009/071500 the compound (A1) of page 21- (A31) mentioned in.
The non-limiting examples of suitable pest repellant and desorbing agent are in the chemical combination of page 21 and 22 of WO 2009/071500 Mentioned in object (R1)-(R3).
The non-limiting examples of suitable synergist are in page 22 of WO 2009/071500 of compound (S1)-(S3) It is mentioned.
Therefore, another importance of the invention is related to the compound artifact for preventing the parasite on warm-blooded animal, It is characterized in that other than the compound of formula (I), they are also containing at least one its with identical or different range activity Its active constituent and at least one physiologically acceptable carrier.The present invention is not limited to double combinations.
In one embodiment of the invention, the compound of formula (I) is combined with one or more other anti-anthelminthics and is made With.Such combination can further reduce the possibility of tolerance generation.Suitable other anti-anthelminthics include.
Embodiment further illustrates the present invention.Thereafter the characterize data use reported in last row of table 1 and 2 has Reversed-phase column (XTerra®, 5 μm of MS C18,50x4.6mm) Waters Autopurification (HPLC/MS) system It obtains.The sample is characterized by m/z and retention time.It is molten comprising two kinds of differences that retention time is related to use in every case Agent (solvent A：H2O+0.01% HCOOH and solvent B：CH3+ 0.01% HCOOH of CN) solvent system.With 2.00 ml/ The flow velocity of min utilizes described two solvent As and B with the time dependence gradient provided in such as following table：
Embodiment 1 (No. 32 in the following table 2)
At 0 DEG C under a nitrogen, by the commercially available 2- chloropyridines -4- phosphinylidynes of the 366mg being dissolved in 2ml dichloromethane Chlorine is added dropwise to the commercially available 4- of 530mg (1- piperazinyls) -2- Trifluoromethylbenzonitriles in 5ml dichloromethane and 630mg Et3Solution in N.Reaction mixture is stirred at room temperature overnight, pours into being stirred for 100ml EtOAc and 40ml water On object.With EtOAc aqueous layer extracteds.The organic layer of merging is washed with brine, through MgSO4Dry, filtering is concentrated under vacuum simultaneously It purifies to detach 620mg 4- { 4- [(2- chloropyridine -4- bases) carbonyl] piperazine -1- bases } -2- (three by the column chromatography on silica gel Methyl fluoride) benzonitrile.Then by 99mg, the substance is added to the commercially available 1- of 85mg (4- trifluoromethyls) piperazine, 6mg Pd (OAc)2、23mg RuPhos、163mg Cs2CO3With the degased mixture of the 1.5ml tert-butyl alcohols, it is then heated to 85 DEG C overnight. Then reaction mixture is poured at room temperature on the stirring mixture of 50ml EtOAc and 10ml water.Extracted with 10ml EtOAc Water intaking layer.The organic layer of merging is washed with brine, through MgSO4Dry, filtering is concentrated under vacuum and is purified by column chromatography To detach the compound N o. 32 in 60mg tables 2.
It is similarly prepared with the above method such as the substance as shown in the following table 1 and 2.
Table 1
Table 2
Following molecule is prepared in a similar manner：
The anti-worm potential of new compound is evaluated in following test：
Stomach-intestines paedomorphosis measures
For being inoculated with proper formatting orifice plate, the orifice plate contains to be assessed anti-post for fresh harvest and the line eggs of cleaning The test substances and permission ovum of infested activity reach full growth to the medium of the 3rd instar larvae.By plate in 25 DEG C and 60% relative humidity It is lower to be incubated 6 days.Egg hatching and subsequent larvae development are recorded to identify possible eelworm-killing activity.Effect reduces with egg hatching, L3 developments reduce or larva represents in the paralysis in any stage and dead percentage.Compound N o. 1,2,3,4,5,6,7,8, 9、10、11、12、13、14、15、17、18、23、24、25、26、27、29、31、32、34、35、36、37、38、39、40、41、42、 43rd, 44 and 46 reach >=60% effect under 10ppm, and are therefore considered effective.
Stomach-intestines worm in gerbil jird
7 or 6 days before treatment, with trichostrongylus colubriformis (T. colubriformisAnd haemonchus contortus (Tc)) (H. contortus(Hc)) respective about 2000 the 3rd instar larvaes pass through gavage artificial challenge gerbil jird.With the test of preparation Compound oral (p.o.) is treated.3 days after treatment, gerbil jird is made to be euthanized and dissect, to recycle twisted blood lance from stomach The top recycling trichostrongylus colubriformis of nematode and therefrom intestines.
Effect is expressed as dropping using the percentage of the worm number compared to placebo treatment group that the formula of Abbot calculates It is low.Compound N o. 1,2,4,5,6,8,11,12,13,15,23,25,31,32,34,42,43 and 44 is at least in 10mg/kg P.o. the display pair in gerbil jird underHcThe effect for being higher than 80%, and compound N o. 2,11,13,43 and 44 is at least in 10mg/ The display pair in gerbil jird under kg p.o.TcThe effect for being higher than 80%, therefore be considered effective.
Heart worm microfilaria measures
The heart worm microfilaria of fresh harvest and cleaning is always prepared from the blood of donor animal kennel.Then by microfilaria Distribution is in microwell plate is formatted, the test substances for formatting microwell plate and containing Antiparasitic Activity to be assessed.Plate is existed It is incubated 48 hours under 25 DEG C and 60% relative humidity (RH).Then the motility of microfilaria is recorded to measure effect.Effect with Compareing the motility compared with standard items reduces percentage expression.It shows and is higher than under each leisure 10ppm of compound N o. 1-46 50% effect, therefore be considered effective.
In gerbil jird dipetalonema viteae (Acanthocheilonema viteae)。
With 80 dipetalonema viteaes (A. viteae) L3 larvas by the way that artificial challenge gerbil jird is subcutaneously injected.It is infecting It is carried out continuously within the 5th day later to the 9th day the treatment for passing through gavage with the test compound prepared.Eight fortnight after infection, Gerbil jird is taken a blood sample, for Fuchs-Rosenthal counting chambers and microscopic counting to be used to recycle microfilaria.Only (it is followed test group 50%) average value of ring microfilaria is lower than placebo treatment group at least fully to be dissected to recycle adult worm.Effect is expressed as The % of the worm number compared to placebo treatment group calculated using the formula of Abbot is reduced.Compound N o. 1 is in 3mg/kg Lower effect of the display higher than 80%.

Claims (14)

1. the compound of following formula or its physiologically acceptable salt
Wherein Z1And Z2It is N or CR each independently1’；
R1And R1’It is H, halogen, cyano, nitro, C independently of one another1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C3Halogenated alkoxy, C1-C4Alkyl sulfenyl, halogenated-C1-C4Alkyl sulfenyl, SF5, amino, N- it is mono--or bis--C of N, N-1- C4Alkyl amino, amino-sulfonyl, N- be mono--or bis--C of N, N-1-C4Alkyl amino sulfonyl, N- be mono--or N, N- bis--halogenated- C1-C4Alkyl amino sulfonyl, C1-C4Alkyl sulphonyl, C1-C4Alkyl sulphinyl, C1-C4Alkyl sulfonyl-amino, halogen Generation-C1-C4Alkyl sulphonyl, halogenated-C1-C4Alkyl sulphinyl, halogenated-C1-C4Alkyl sulfonyl-amino or benzyl sulphonyl Base amino；
Q is Ar1Or-C (O)-(O)m-R2；
M is 0 or 1；R2It is C1-C6Alkyl or C3-C8Cycloalkyl；
Ar1It is (i) by the 1 or 2 identical or different phenyl replaced selected from following substituent group：Halogen, cyano, nitro, C1-C4Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkyl sulfenyl, halogenated-C1- C4Alkyl sulfenyl, SF5, amino, N- it is mono--or bis--C of N, N-1-C4Alkyl amino, amino-sulfonyl, N- be mono--or bis--C of N, N-1- C4Alkyl amino sulfonyl, N- be mono--or N, N- bis--halogenated-C1-C4Alkyl amino sulfonyl, C1-C4Alkyl sulphonyl, C1- C4Alkyl sulphinyl, C1-C4Alkyl sulfonyl-amino, benzylsulphonyl amino, halogenated-C1-C4Alkyl sulphonyl, it is halogenated- C1-C4Alkyl sulphinyl and halogenated dioxa cyclopentenyl；Or (ii) heteroaryl, selected from 2-, 3- or 4- pyridyl group and 2- or 3- thienyls, it is respectively unsubstituted or by methyl, ethyl, halogen, CF3Or carboxyl substitution；
Ar2It is by 1 to 3 identical or different phenyl replaced selected from following substituent group：Halogen, cyano, nitro, C1-C4- Alkyl, C1-C4Halogenated alkyl, C1-C4Alkoxy, C1-C4Halogenated alkoxy, C1-C4Alkyl sulfenyl, halogenated-C1-C4Alkyl Sulfenyl, SF5, amino, N- it is mono--or bis--C of N, N-1-C4Alkyl amino, amino-sulfonyl, N- be mono--or bis--C of N, N-1-C4Alkyl Amino-sulfonyl, N- be mono--or N, N- bis--halogenated-C1-C4Alkyl amino sulfonyl, C1-C4Alkyl sulphonyl, C1-C4Alkyl Sulfinyl, C1-C4Alkyl sulfonyl-amino, benzylsulphonyl amino, halogenated-C1-C4Alkyl sulphonyl, halogenated-C1-C4- Alkyl sulphinyl and halogenated dioxa cyclopentenyl；
L1It is the bifunctional linker group of following formula
L2It is the bifunctional linker group of following formula
A and B is the C for including two N- atoms respectively each independently3-C8Miscellaneous-cycloalkylidene or C5-C10Miscellaneous-sub- bicyclic alkane Base, it is respectively unsubstituted or by C1-C2Alkyl replaces；
A1、A2、B1And B2It is the C for including N- atoms respectively each independently3-C8Miscellaneous-cycloalkylidene；
R and R' is H or C independently of one another1-C4Alkyl.
2. compound according to claim 1, wherein R1And R1’It is H, cyano, methyl or methoxy independently of one another.
3. compound according to claim 1, wherein Z1It is N and Z2It is CR1’。
4. according to the compound of any one of claims 1 to 3, wherein Q is Ar1And Ar1It is identical or different by 1 or 2 Selected from halogen, cyano and C1-C2The phenyl of the group substitution of halogenated alkyl.
5. according to the compound of any one of claims 1 to 3, wherein Q is group-C (O)-(O)m-R2, wherein R2It is C1-C4- Alkyl or C3-C6Cycloalkyl.
6. according to the compound of any one of claims 1 to 3, wherein Ar2It is identical or different selected from halogen by 1 or 2 Element, cyano, nitro, C1-C2Halogenated alkyl, C1-C2Halogenated alkoxy or C1-C2The benzene of the group substitution of haloalkylthio Base.
7. according to the compound of any one of claims 1 to 3, wherein the linker L1With following formula
Wherein s and r is integer 1 or 2 each independently, and r' is integer 0,1 or 2, s' are integer 0,1 or 2 and R is H or methyl.
8. according to the compound of any one of claims 1 to 3, wherein the linker L2It is the group of following formula：
Wherein r'' is 0 or 1, s' are integer 1 or 2 and R' is H or methyl.
9. according to the compound of any one of claims 1 to 3, wherein L1It is group, and L2It is group。
10. compound according to claim 1, with following formula
Wherein R1、R2、m、L1、L2、Z1、Z2And Ar2Respectively as defined in claim 1.
11. compound according to claim 1, with following formula
Wherein R1、Ar1、Ar2、L1、L2、Z1And Z2Respectively as defined in claim 1.
12. compound according to claim 1 or its physiologically acceptable salt, the compound has following formula
Wherein Q is 4-CF3Phenyl, 5-CF3Pyridine -2- bases, 6-CF3Pyridin-3-yl ,-C (O)-O- tertiary butyls or-C (O)-ring Propyl；
Z1It is N or CH；
Z2It is N or CH；
L1It is group；
L2It is group
R3It is CF3；And R3’It is cyano or nitro.
13. for preventing the composition of parasite, the composition also contains other than carrier and/or dispersant as work Property ingredient at least one compound according to any one of claims 1 to 12.
14. compound is used to prepare the beast of the endoparasite in anti-warm-blooded animal according to any one of claims 1 to 12 With composition or the purposes of pharmaceutical composition.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009080203A2 (en) * 2007-12-21 2009-07-02 Bayer Cropscience Ag Aminobenzamide derivatives as useful agents for controlling animal parasites
CN102414197A (en) * 2009-04-27 2012-04-11 美国陶氏益农公司 Insecticidal pyridine compounds
WO2012163959A1 (en) * 2011-05-31 2012-12-06 Syngenta Participations Ag Insecticidal compounds

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2006297089B2 (en) * 2005-09-27 2012-05-03 Irm Llc Diarylamine-containing compounds and compositions, and their use as modulators of c-kit receptors
WO2009071500A2 (en) 2007-12-03 2009-06-11 Novartis Ag Organic compounds
JP2011524365A (en) * 2008-06-11 2011-09-01 アイアールエム・リミテッド・ライアビリティ・カンパニー Compounds and compositions useful for the treatment of malaria
EP2569298B1 (en) 2010-05-12 2015-11-25 Boehringer Ingelheim International GmbH Novel ccr2 receptor antagonists, method for producing the same, and use thereof as medicaments
WO2013182612A1 (en) * 2012-06-07 2013-12-12 Bayer Pharma Aktiengesellschaft Glucose transport inhibitors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009080203A2 (en) * 2007-12-21 2009-07-02 Bayer Cropscience Ag Aminobenzamide derivatives as useful agents for controlling animal parasites
CN102414197A (en) * 2009-04-27 2012-04-11 美国陶氏益农公司 Insecticidal pyridine compounds
WO2012163959A1 (en) * 2011-05-31 2012-12-06 Syngenta Participations Ag Insecticidal compounds

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